Colorectal cancer is a major public health problem in the Western world and ranks as the third leading cause of death in both males and females. In 2000, more than 9000 new colorectal cancer patients were registered in the Netherlands, of whom 25% had rectal cancer. Rectal cancer is a disease in which malignant (cancer) cells form in the tissues of the rectum.
The term locally advanced rectal cancer (LARC) encompasses rectal tumors that by clinical or radiological assessment grow through the rectal wall to an extent that complete removal by surgery alone is considered impossible. Using TNM classification, a cancer staging system for the classification of malignant tumours, the extent of cancer in a patient's body is described. LARC is typically staged as a T3 or T4 tumor, and involves the mesorectal compartment or infiltrates adjacent pelvic structures respectively.
Relapses from rectal cancer following primary treatment occur as local recurrences or distant metastases, mainly to liver or lungs. Local recurrences arise if primary treatment has not resulted in local control, whereas distant metastases develop because of dissemination of tumor cells by lymphatic or blood circulation.
A major problem in LARC is the thread of local recurrence, not only because of the limited therapeutic options but especially because of the impaired quality of life due to the intense pain and uncontrolled soiling. There are therefore four major goals in the treatment of a patient with rectal cancer: (1) local control; (2) long-term survival; (3) preservation of anal sphincter, bladder, and sexual function; and (4) maintenance or improvement in quality of life.
Randomized trials have shown that the best local control rate for rectal cancer patients is achieved after a short course of radiation and chemotherapy followed by optimal surgery. The addition of this preoperative chemoradiotherapy has changed the treatment of LARC dramatically as shown in several trials showing improvements over traditional removal of the tumor without preoperative treatment. Thus the standard treatment of LARC is multimodal, involving preoperative chemoradiotherapy aimed at down-staging the tumor to allow subsequent complete surgical removal or resection. The chemotherapy component of this therapeutic strategy is intended to sensitize the tumor to ionizing radiation. However, radiation therapy also causes damage to healthy tissues, which confers the risk of short- and long-term complications.
An important factor when performing radiation treatment is that the response to chemoradiotherapy varies greatly, from complete response with no remaining tumor tissue, observed in 0-30% of patients, to no objective response. Hence, it would be useful to select and treat only those patients likely to benefit from preoperative chemoradiotherapy. The identified non-responders are at that point candidates for other treatments like alternative radiosensitizing regimens.
At present no clinical or analytical tools are available to make the distinction between responders and non-responders prior to deciding which treatment to administer although a few attempts of predictive biomarkers have been described in the literature such as Smac expression (assessed by immunohistochemistry), epidermal growth factor receptor expression (assessed by immunohistochemistry) and c-K-ras gene mutations. These methods are however highly variable, not robust and show poor predictivity since these screenings are based on the detection of a limited number of proteins or genes and a small variation in the gene or protein expression will have profound effects on the screening method.
In view of the above, there remains a pressing need for methods that provide a fast and accurate prediction of the response of a patient diagnosed with rectal cancer to induction chemoradiotherapy. These methods would enable to provide information regarding the efficacy of the preoperative chemoradiotherapy treatment, and more specifically provide an early determination of the most suited treatment of the rectal cancer patient.
The present invention aims at providing methods and devices for predicting the response of a patient diagnosed with rectal cancer to induction chemoradiotherapy. The present invention also aims to provide methods and devices for predicting the response of patients diagnosed with rectal cancer to specific medicaments, radiotherapy and/or chemotherapy treatments. The method of the present invention therefore adds to the existing assays currently used to select therapies in rectal cancer patients.